Decarboxylation of amino acids is an important synthetic route to biologically active amines and other useful byproducts. Current procedures for synthesis of biologically relevant amines often suffer from extremely long reaction times, can require high boiling point solvents and extremely high reaction temperatures, and difficulty with solvent and byproduct removal.
Decarboxylation of amino acids is a long-known reaction for the production of biologically active amines and their derivatives, which find multiple applications. Some conventional methods involves high-temperature thermolysis of the amino acid in specific solvents in the presence of a catalytic amount of a carbonyl-containing compound such as an aldehyde or ketone, commonly involving catalysts wherein the carbonyl group is close to (or conjugated with) an insaturation, such as a carbon-carbon double bond. (Chatelus, G. Bull. Soc. Chim. Fr. (1964), 2533; Hashimoto, M et al, (1986) Chem, Lett., 6, 893; Wallbaum, S. et al., (1994), J. Synth. Commun., 24, 1381; Hashimoto, M. et al., (1986) Chem. Lett. 15(6), 893-896). However, these methods can involve extreme high temperatures, long reaction times, and solvents that can withstand such temperatures, many of which are toxic or present problems with later solvent removal.
An example of a method directed at the deficiencies of traditional routes for the decarboxylation of amino acids is given by Laval and Golding (G. Laval and B. T. Golding: One-pot sequence for the Decarboxylation of α-amino acids. (2003). Synlet, 4, 542-546), where the treatment of an α-amino acid, at room temperature, with N-bromosuccinimide (NBS) in aqueous phosphate buffer at pH 5 (or in a solution of NH4Cl in ethanol/water), followed by addition of NiCl2.6H2O and NaBH4 led to the decarboxylation—via an intermediate nitrile—to yield the corresponding amine in 59% to 81% yield (depending on the starting amino acid). Laval's method was shown to be effective in conjunction with both natural and unnatural α-amino acids, including carboxypolyamines and those amino acids decorated with other functionalities such as CF3, NHR, NR2, and H3C—S (e.g., methionine). While Laval's method is carried out in water at room temperature and pressure, it involves the use of toxic NBS and will require proper disposal of metal-, bromide- and boron-containing reaction by-products.
More recently, Zhou described a one-pot, aldehyde-induced, metal-free process for the decarboxylation of α-amino acids to synthesize N-alkyl-f-alkenyl cyclic amines with high stereoselectivity (Zhou, J. et al, (2017) Tetrahedron Lett, 58, 3174-3177). By varying reaction conditions, decarboxylation reactions were achieved in up to 62%. The end-products of Zhou's method, however, are not the corresponding free amines but rather N-alkyl-β-alkenyl cyclic amines.
Industrial production of amines by bio-fermentative routes (e.g., biogenic amine production by lactic acid bacteria), on the other hand, is limited to the production of naturally occurring amines and the production of amines derived from unnatural amino acids is not achieved by such means.
Thus, there is the need for an alternative method for the high-yield production and isolation of free amines that is fast, solvent-free, allows for the easy recovery of reagents, is employable in conjunction with both natural and unnatural amino acids, and provides for the recovery of useful and commercially important byproduct(s).